Definition and Processes of Pharmacokinetics

How a drug works and what happens to it upon entering the body are important factors in drug design, in order to ensure optimal action in the desired amount of time. Drugs are absorbed from the site of administration into the systemic circulation, where they may interact with the proteins; they then reach their target tissues, changed or unchanged, and act on them. The moment a drug enters the systemic circulation, it starts to be simultaneously eliminated by certain biological processes. All these together constitute pharmacokinetics of the drug.

Definition of Pharmacokinetics

Pharmacokinetics is the movement of a drug through the body’s biological systems, these processes include absorption, distribution, metabolism and elimination.

Absorption of Drugs

To reach its target tissue, a drug must enter the systemic circulation, this includes being introduced directly into the blood (intravenous or intra-arterial administration), absorbed through the skin, and though the digestive system.

Blood flow, the concentration of the drug at the administered site, and the route of administration (see the section on bioavailability in Elimination Kinetics notes) are important factors that affect the absorption of the drug. In the case of oral administration, local pH and gastrointestinal contents can affect the absorption.

Important: Intravenous administration provides 100 % bioavailability.

Cell Membrane

Cell membranes have a phospholipid bilayer, with the hydrophilic heads of the each of the phospholipid layers facing outwards and the lipophilic ends facing inwards. Embedded throughout the span of this bilayer are glycoproteins; these glycoproteins act as ion channels, receptors, secondary messengers (G-proteins), or enzymes. Some tissues have a slightly modified cell membrane for more specialized functions. For example:

In the capillary endothelium, there are regions where the outer and inner membranes are fused together with no intervening cytosol—called fenestrae—which make the endothelium relatively permeable, especially to fluid.

In the glomerular endothelium, there are gaps/clefts between cells; this permits larger molecules to filter through.

The blood–brain barrier (BBB) limits the passage of certain molecules (polar drugs) and proteins across the two fluid compartments.

“Cell Membrane” Image created by Lecturio

Transportation of drugs

A drug is absorbed from the site of administration (e.g., the gastrointestinal tract) by passive diffusion or active transportation, depending on the physicochemical properties of the drug.

For example, small lipid- or water- soluble drugs can move across the plasma membrane (through the membrane bilayers or aqueous channels/pores, respectively). This is called simple passive diffusion. Some drugs require specialized transmembrane carrier proteins to aid their passage across the cell membrane. This is called facilitated diffusion.

Some drugs need to be actively transported across the cell membrane by a carrier protein, a process that uses energy (usually in the form of ATP). This is called active transport. This usually occurs for drugs that are structurally similar to endogenous molecules, such as vitamins, sugars, and amino acids.

Drugs of very large sizes are transported by engulfment of the drug molecule by the cell membrane, which is transported inside the cell; this process is called endocytosis. This vesicle can either be used in the cell (e.g., iron), pushed across the cell (e.g., vitamin B12), or stored for later use (e.g., neurotransmitters).

All pharmacokinetic processes involve transport of the drug across the cell membrane.

Aqueous and lipid diffusion

Image: “Diffusion from a microscopic and macroscopic point of view. Initially, there are solute molecules on the left side of a barrier (purple line) and none on the right. The barrier is removed, and the solute diffuses to fill the whole container. Top: A single molecule moves around randomly. Middle: With more molecules, there is a clear trend where the solute fills the container more and more evenly. Bottom: With an enormous number of solute molecules, the randomness is gone: The solute appears to move smoothly and systematically from high-concentration areas to low-concentration areas, following Fick’s laws. ”

Both aqueous diffusion and lipid diffusion are types of simple passive diffusion and are governed by Fick’s law of diffusion: molecules are diffused from a region of high concentration to a region of low concentration until equilibrium is achieved.

Aqueous diffusion

Occurs through aqueous pores that are found in most cell membranes

Water-soluble drugs can pass along concentration gradient

Permits small molecules to pass through easily

Some tissues, e.g., the brain, testes, lack aqueous pores

Charged molecules pass more readily through pores because they are attracted by water molecules in pores

Protein-bound drugs cannot permeate through pores

Lipid diffusion

Occurs directly across cell membrane

Lipid-soluble drugs pass along concentration gradient

Uncharged drugs cross membranes more easily than charged drugs, thus, ionization of a drug will reduce its ability to cross membrane

Examples of acidic drugs and basic drugs

Acidic drugs

Basic drugs

Phenytoin

Pentobarbital

Aspirin

Ibuprofen

Cloxacillin

Ethosuximide

Caffeine

Theophylline

Codeine

Amitryptyline

Drug pKa and solubility

As mentioned, ionization of the drug affects its transportation across the cell membrane. The amount of the ionized form present depends on the environmental pH (of the stomach, for example) and the pKa of the drug.

The pKa of the drug is the pH at which the ionized and unionized forms of the drug are present in equal amounts. If the pH and the pKa are known, the fraction of the drug present in ionized state can be calculated by the Henderson–Hasselbalch equation. The ionized form of the drug is water soluble and non-ionized form of the drug is lipid soluble. The ionization of the drug increases its renal clearance.

Making urine more alkaline (i.e. by giving intravenous sodium bicarbonate) can increase excretion of acidic drugs such as aspirin, barbiturates, and methotrexate. Alkalization also increases the ionization of drugs, which results in enhanced solubility of the acidic drug and consequently rapid elimination from the body. Thus, it helps in the treatment of drug overdose.

Important: Normal pH of urine is 6.0, through alkalization; the pH of urine can increase up to 7.5.

Acidification of urine (i.e. by giving IV ascorbic acid or ammonium chloride) increases the excretion of basic drugs such as caffeine, cocaine, and amphetamine. Similarly, acidification of urine increases the ionization of drugs which results in enhanced solubility of a basic drug and consequently rapid elimination from the body.

Important: Normal pH of urine is 6.0, through acidification; the pH of urine can decrease to 5.0.

Distribution of Drugs

After entering the systemic circulating, a drug is distributed and eliminated, often at the same time. The body has a multi-fluid compartment structure, and the drug can be distributed in any or all of those compartments:

Peripheral compartment: Tissues with lesser blood flow (e.g., fat and muscle tissues); drugs that are stored in fat, for example, take a long time to equilibrate and the tissues can act as a reservoir, e.g., thiopental sodium

Drugs can be bound to plasma proteins. Only the free (unbound) drug is available to act on the cell membranes of the target tissues. Protein binding must be taken into account when interpreting the concentration of a drug in the blood. This means a high concentration does not necessarily mean the drug is highly active, since only a small portion may be unbound while the rest is bound to protein.

Key points of protein binding

Irreversible binding of drugs can result in toxicity (e.g., irreversible binding of paracetamol metabolites to the hepatocytes)

Most drugs bind to human serum albumin (HSA); it’s also the most abundant plasma protein

HSA has 4 drug binding sites

Competition between 2 drugs for same binding site on HSA can result in displacement interactions; displaced drugs can cause increased toxicity (e.g., when phenylbutazone & warfarin are administered simultaneously, phenylbutazone displaces warfarin from HSA because of its higher affinity to HSA and the displaced warfarin can increase blood loss)

Decreased protein binding of a drug can result in its increased metabolism/elimination from body

Increased concentration of free drug in body can result in toxicity or increased therapeutic action

Barriers to distribution of drugs

CSF barrier

Blood-brain barrier

Placental barrier

Blood-testis barrier

Volume of distribution

The apparent volume of distribution (Vd) is defined as the volume of fluid required to contain the amount of the drug present in the body at the same concentration as measured in the plasma.

Vd = total amount of the drug administered/drug concentration of the blood

Note that Vd does not represent an actual volume (it is a theoretical value); it is an indicator of the amount of body fluid that would be required if the drug were distributed equally throughout the body.

Biotransformation

Elimination

Drug Development

Development of a new drug can take around 10–15 years and can cost billions of dollars. Most of drugs fail in early clinical trials either due to toxicity or solubility/stability issues. There are several steps in the development of novel drugs.

Image: “Graph showing the various approval tracks and research phases” by Kernsters. License: CC BY-SA 3.0

Step 1: Drug discovery and development

After the discovery of the drug through rigorous testing, the drug is tested for its physiochemical, pharmacokinetic, and pharmacodynamic properties.

Step 2:Preclinical research

In vivo and in vitro testing to determine toxicity is done in animals.

Step 3:Clinical research

Phase I trial: Performed in healthy volunteers (20–250) to determine safety and efficacy

Phase II trial: Further explore safety and efficacy in a small number (100–250) of patients with the disease

Phase III trial: Compare the new drug’s efficacy to commonly used treatments and record adverse effects in a large group of patients (1000–6000) with the disease

Phase IV trial: Long-term use in a large group of people, often as post-marketing surveillance

Step 4:FDA review (NDA) and approval/rejection

Step 5:FDA post-marketing surveillance

The adverse effects (ADRs) not detected during clinical trials are reported to the FDA in the post-marketing surveillance phase.

Important terms

IND: Investigational new drug application, an application filed to the FDA to seek the approval to start the clinical trials of a new drug on humans

NDA: New drug application, an application seeking final approval of a drug by FDA to market in the USA

Single and double blind study: A study in which a physician knows which patients are receiving active drug and placebo is called single blind study. A study in which neither of the physician and patient know which patients are receiving active drug and placebo is called double blind study.

ANDA: Abbreviated new drug application, an application seeking final approval of a drug whose patent has been expired (generic drug) by FDA to market in the USA. Sponsor of a drug has to prove the bioequivalence to the reference listed drug

Orphan drug: A drug which is used to treat a disease which affects only 200,000 people in the USA

Blockbuster drug: A drug which generates revenue of more than $1 billion dollars annually for a pharmaceutical company (e.g., Lipitor and Viagra)

FDA: Food and drug administration, drug regulatory body of the USA

Review Questions

The correct answers can be found below the references.

1. A mildly overweight woman in her late 20s was taking depot-medroxyprogesterone acetate (DMPA) for several years as an oral contraceptive. She stopped taking it when she got married. Five years later, she went on a diet and exercise regimen and lost 6 kg. At that time, she had some episodes of irregular bleeding—the same symptoms that she used to have while taking DMPA. What was the probable cause?

2. A new antihypertensive drug is being tested in a small group of patients with mild-to-moderate hypertension. Which phase of the clinical trial is the drug in?

Phase I

Phase II

Phase III

Phase IV

3. A man weighing 60 kg is given a 250 mg dose of a drug intravenously. On measuring the plasma concentration, the value is found to be 20 mg/L. What is the value of the apparent volume of distribution of this drug?

5000

0.08

5

750

12.5

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